4F2Y

Structure of 3'-Fluoro Cyclohexenyl Nucleic Acid Decamer

Summary for 4F2Y

• Entry DOI: 10.2210/pdb4f2y/pdb
• Related: 4F2X
• Descriptor: 5'-D(*GP*CP*GP*TP*AP*(XTF)P*AP*CP*GP*C)-3', MAGNESIUM ION (3 entities in total)
• Functional Keywords: fluoro cyclohexenyl nucleic acid, f-cena, modified dna, a-form dna, dna
• Total number of polymer chains: 2
• Total formula weight: 6194.68

Authors

Pallan, P.S.,Egli, M. (deposition date: 2012-05-08, release date: 2012-05-30, Last modification date: 2023-09-13)

Primary citation

Seth, P.P.,Yu, J.,Jazayeri, A.,Pallan, P.S.,Allerson, C.R.,Ostergaard, M.E.,Liu, F.,Herdewijn, P.,Egli, M.,Swayze, E.E.
Synthesis and Antisense Properties of Fluoro Cyclohexenyl Nucleic Acid (F-CeNA), a Nuclease Stable Mimic of 2'-Fluoro RNA.
J.Org.Chem., 77:5074-5085, 2012

PubMed Abstract: We report the design and synthesis of 2'-fluoro cyclohexenyl nucleic acid (F-CeNA) pyrimidine phosphoramidites and the synthesis and biophysical, structural, and biological evaluation of modified oligonucleotides. The synthesis of the nucleoside phosphoramidites was accomplished in multigram quantities starting from commercially available methyl-D-mannose pyranoside. Installation of the fluorine atom was accomplished using nonafluorobutanesulfonyl fluoride, and the cyclohexenyl ring system was assembled by means of a palladium-catalyzed Ferrier rearrangement. Installation of the nucleobase was carried out under Mitsunobu conditions followed by standard protecting group manipulations to provide the desired pyrimidine phosphoramidites. Biophysical evaluation indicated that F-CeNA shows behavior similar to that of a 2'-modified nucleotide, and duplexes with RNA showed slightly lower duplex thermostability as compared to that of the more rigid 3'-fluoro hexitol nucleic acid (FHNA). However, F-CeNA modified oligonucleotides were significantly more stable against digestion by snake venom phosphodiesterases (SVPD) as compared to unmodified DNA, 2'-fluoro RNA (FRNA), 2'-methoxyethyl RNA (MOE), and FHNA modified oligonucleotides. Examination of crystal structures of a modified DNA heptamer duplex d(GCG)-T*-d(GCG):d(CGCACGC) by X-ray crystallography indicated that the cyclohexenyl ring system exhibits both the (3)H(2) and (2)H(3) conformations, similar to the C3'-endo/C2'-endo conformation equilibrium seen in natural furanose nucleosides. In the (2)H(3) conformation, the equatorial fluorine engages in a relatively close contact with C8 (2.94 Å) of the 3'-adjacent dG nucleotide that may represent a pseudo hydrogen bond. In contrast, the cyclohexenyl ring of F-CeNA was found to exist exclusively in the (3)H(2) (C3'-endo like) conformation in the crystal structure of the modified A-form DNA decamer duplex [d(GCGTA)-T*-d(ACGC)](2.) In an animal experiment, a 16-mer F-CeNA gapmer ASO showed similar RNA affinity but significantly improved activity compared to that of a sequence matched MOE ASO, thus establishing F-CeNA as a useful modification for antisense applications.

PubMed: 22591005
DOI: 10.1021/jo300594b

Experimental method

X-RAY DIFFRACTION (1.59 Å)